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Local anesthetics 1
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LOCAL LOCAL ANESTHETICSANESTHETICS
Local AnestheticsDEFINITION
Drugs which– produce a REVERSIBLE loss of sensation …– in a localized part of the body…..– when applied directly onto nerve tissues
or mucous membranes
Local anesthetics are ‘local’ ONLY because of how they are administered! (Selectivity)
The first clinically used Local Anesthetic
Cocaine (ISA activity)
A natural alkaloid from Erythroxylon coca.
Prototype Drug Lignocaine (Synthetic)
Properties Desirable in a Local Anesthetic
Non-irritating Do not cause permanent damage to nerve structure Systemic toxicity should be low Effective
InjectedApplied locally
Onset of action as short as possible DOA long enough to allow time for counter plated surgery
CLASSIFICATION ACCORDING TO CLASSIFICATION ACCORDING TO CHEMISTRY CHEMISTRY
ESTERS Cocaine Procaine Tetracaine Benzocaine
(Contd)
AMIDES Lignocaine/Lidocaine Bupivacaine LevobupivacaineMepivacaine Prilocaine Etidocaine Ropivacaine
2. According to Duration of 2. According to Duration of actionaction
Short Duration of Action
Procaine
Medium Duration of Action
Cocaine, Lidocaine, Mepivacaine, Prilocaine
Long Duration of Action
Tetracaine, Bupivacaine, Etidocaine, Ropivacaine
CLASSIFICATION ACCORDING TO CLASSIFICATION ACCORDING TO CLINCIAL USESCLINCIAL USES
SURFACE ANESTHESIASURFACE ANESTHESIA
INFILTRATION ANESTHESIA & FIELD INFILTRATION ANESTHESIA & FIELD BLOCK ANESTHESIABLOCK ANESTHESIA Lignocaine Procaine Bupivacaine
Tetracaine Lignocaine CocaineBenzocaine
NERVE BLOCK ANESTHESIANERVE BLOCK ANESTHESIA
Procaine
Lignocaine
Bupivacaine
Tetracaine
Ropivacaine
SPINAL ANESTHESIA SPINAL ANESTHESIA Lignocaine
Tetracaine
Bupivacaine
EPIDURAL ANESTHESIA Lignocaine Bupivacaine
ANESTHETIC USED IN OPHTHALMOLOGY Proparacaine
ChemistryChemistryMost local anesthetics consist of 3 partsMost local anesthetics consist of 3 parts
1. Lipophilic Aromatic group
2. Intermediate chain
3. Hydrophilic Amino group
C
LAs - Weak Bases (pKa:7.5-9)
C O
O
R N
R
R
NH
O
R N
R
R
Aromatic portion Amine portion
Intermediate chain
ESTER
AMIDE
LIPOPHILIC HYDROPHILIC
Two types of linkages give rise to 2 chemical classes of local
anesthetics. ESTER LINKAGE AMIDE LINKAGE
PROCAINE
procaine (Novocaine)
tetracaine (Pontocaine)
benzocaine
cocaine
LIDOCAINE
lidocaine (Xylocaine)
mepivacaine (Carbocaine)
bupivacaine (Marcaine)
etidocaine (Duranest)
ropivacaine (Naropin)
MECHANISM OF ACTION Diffusion into the nerve fiber Blockade of sodium channels
Mem
bran
e P
oten
tial
(m
V)
-50
-70
0
+30
Time (msec)
ThresholdPotential
ThresholdPotential
Resting MembranePotential
Resting MembranePotential
Na+ equilibriumNa+ equilibriumAction
Potential
ActionPotential
Depolarization!Depolarization!
HyperpolarizedHyperpolarized
+ 40 mv
Na+ influx K+ efflux
+ +
- -
+ +
--
- -
+ + + +
- -
Na+
+ ++ +
- - - -
Resting (Closed**)
Open
(brief)
inactivated
Very slow repolarization in presence of LA
LA receptor
LA have highest affinity for the inactivated formRefractory period
**Closed state may exist in various forms as it moves from resting to open. LA have a high affinity for the different closed forms and may prevent them from opening.
Progressively increasing conc. of a LA applied to a nerve fiber produce blockade of more & more Na+ channels :
The threshold for excitation increases Impulse conduction slows The rate of rise of AP declines The AP amplitude decreases Finally the ability to generate an AP is abolished
SUSCEPTIBILITY OF NERVE FIBER TO LA
Potency Size of nerve fiber (small fibers blocked 1st) Effect of fiber diameter Rate of firing (rapidly firing fibers blocked
1st) Effect of fiber position in the nerve bundle
(outer fibers blocked 1st, then core fibers)
ORDER OF BLOCKADE
AUTONOMIC PAIN TEMPERATURE TOUCH DEEP PRESSURE MOTOR
Recovery in reverse orderRecovery in reverse order
PHARMACOKINETICS Absorption
Dosage
Site of injection (when used for major conduction blocks, the peak serum levels will vary as a function of the specific site of injection, with intercostal blocks among the highest, & sciatic & femoral among the lowest)
Lipid solubility (more lipid soluble – longer DOA)
PHARMACOKINETICS Ph
Vascularity (highly vascular area – more rapid absorption – higher blood levels)
Combination with vasoconstrictors (resultant reduction in blood flow reduces rate of systemic absorption & diminishes peak serum levels)
Distribution Biotransformation & Excretion
Comparison of LA characteristics
Relative lipid solubility
Relative potency
onset
pKa Local duration
vasodilation
Plasma protein binding
procaine 1 1 slow 8.9 short +++ 5%
lidocaine 4 4 rapid
7.9 moderate
+++ 55%
tetracaine
80 16 slow 8.5 long + 75%
bupivacaine
130 16 slow 8.1 long + 90%
Plasma protein binding may be used as an indirect measure of tissue binding tendencies
ADVERSE EFFECTS CNS (1st stimulation, then depression) Local Neurotoxicity (cauda equina syndrome
associated with continuous spinal anesthesia – CSA) CVS (bupivacaine – most cardiotoxic) ANS Motor Paralysis Hematological Effects Hypersensitivity reactions
Prevention of Toxicity Enquire about history of allergy. Caution in presence of liver/myocardial damage. Proper site (correct knowledge of nerve course). Minimal effective dose usage (avoid I/V adm). Wait after injection. Observe the face for any twitching, excitement, and pulse
for tachycardia. Observe post – op for allergic reactions. Avoid food intake at least 04 hrs prior to anesthesia to
prevent vomiting.
Cocaine Medical use limited to surface or topical
anesthesia
Avoid epinephrine because cocaine already has vasoconstrictor properties. (EXCEPTION!!!)
A toxic action on heart may induce rapid and lethal cardiac failure.
A marked pyrexia is associated with cocaine overdose.
SELECTIVE PHARMACOLOGICAL
Benzocaine– pKa ~ 3, – Available in many preps for relief of pain
and irritation– for surface anesthesia (topical) only ...
ointments, sprays, etc.– Used to produce anesthesia of mucous
membranes – methemoglobinemia
SELECTIVE PHARMACOLOGICAL PROPERTIES OF
SOME AMIDE - type LA LIDOCAINE (Xylocaine) Most widely
used LA– Effective by all routes. – Faster onset, more intense, longer lasting,
than procaine. – Good alternative for those allergic to ester
type – More potent than procaine but about equal
toxicity– More sedative than others
SELECTIVE PHARMACOLOGICAL PROPERTIES OF
SOME AMIDE - type LA Bupivacaine (Marcaine)
– No topical effectiveness– Slower onset and one of the longer
duration agents– Unique property of sensory and motor
dissociation can provide sensory analgesia with minimal motor block has been popular drug for analgesia during
labor
– More cardiotoxic than other LA
SELECTIVE PHARMACOLOGICAL PROPERTIES OF
SOME AMIDE - type LA Ropivacaine
– Enantiomer of bupivacaine (S stereoisomer)– No topical effectiveness– Clinically ~ equivalent to bupivacaine– Similar sensory versus motor selectivity
as bupivacaine with significantly less CV toxicity
CLINICAL APPLICATIONS
SURFACE ANESTHESIA (Topical)– Ear,Nose, mouth, bronchial tree,
nasopharynx,cornea, GIT and urinary tracts Lidocaine, tetracaine, Benzocaine EMLA cream
(Eutectic Mixture of Local Anesthetics) lidocaine 2.5% + prilocaine 2.5% permits anesthetic penetration of keratinized layer of skin as deep as 5mm, producing localized numbness.
Clinical Applications
INFILTRATION ANESTHESIA– Direct injection into tissues to reach nerve
branches and terminals. – Can be superficial as well as deep.– Used in minor surgery. – Immediate onset with variable duration.– This type involve skin region as deep as
intraabdominal tissue.
.Most LA’s used
Clinical Applications
NERVE BLOCK or FIELD BLOCK – Interruption of nerve conduction upon
injection into the region of nerve plexus or trunk.
– Used for surgery, dentistry, analgesia.– Less anesthetic needed than for infiltration– Given within specific nerve area such as
brachial plexus, within intercostal nerves,abdominal nerves are targeted, cervical plexus when neck region is targeted..Most LA’s used
Clinical Applications
SPINAL ANESTHESIA– Injection into subarachnoid space below level
of L2 vertebra to produce effect in spinal roots and spinal cord.
– Use hyperbaric or hypobaric solutions depending on area of blockade.
– Used for surgery to abdomen, pelvis or leg when can’t use general anesthesia.
– Can be employed in pts of hepatic, renal & CVS diseases Lidocaine, tetracaine
Clinical Applications EPIDURAL AND CAUDAL ANESTHESIA
– Injection into epidural space usually at lumbar or sacral levels or near dura matter where nearly most nerves pass closely. Areas supplied by these nerves are targeted e.g.
.ligamentum flavum(post)
.spinal periosteum(laterally), dura(ant).– Lower part of the body. Pelvic region
– For painless child birth.
Clinical Applications
– Unwanted effects similar to that of spinal (pain, hematoma, introduction of foreign particle, hypotension – Rx: raise foot-end of bed or give sympathomimetics, headache – Rx: small bore needle & blood patch, cauda equina syndrome, rarely respiratory paralysis)
Lidocaine, bupivacaine, ropivacaine
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